Publication

Increased miR-142-3p Expression Might Explain Reduced Regulatory T Cell Function in Granulomatosis With Polyangiitis

Dekkema, G. J., Bijma, T., Jellema, P. G., Van Den Berg, A., Kroesen, B-J., Stegeman, C. A., Heeringa, P., Abdulahad, W. H. & Sanders, J-S., 12-Sep-2019, In : Frontiers in Immunology. 10, 12 p., 2170.

Research output: Contribution to journalArticleAcademicpeer-review

APA

Dekkema, G. J., Bijma, T., Jellema, P. G., Van Den Berg, A., Kroesen, B-J., Stegeman, C. A., ... Sanders, J-S. (2019). Increased miR-142-3p Expression Might Explain Reduced Regulatory T Cell Function in Granulomatosis With Polyangiitis. Frontiers in Immunology, 10, [2170]. https://doi.org/10.3389/fimmu.2019.02170

Author

Dekkema, Gerjan J. ; Bijma, Theo ; Jellema, Pytrick G. ; Van Den Berg, Anke ; Kroesen, Bart-Jan ; Stegeman, Coen A. ; Heeringa, Peter ; Abdulahad, Wayel H. ; Sanders, Jan-Stephan. / Increased miR-142-3p Expression Might Explain Reduced Regulatory T Cell Function in Granulomatosis With Polyangiitis. In: Frontiers in Immunology. 2019 ; Vol. 10.

Harvard

Dekkema, GJ, Bijma, T, Jellema, PG, Van Den Berg, A, Kroesen, B-J, Stegeman, CA, Heeringa, P, Abdulahad, WH & Sanders, J-S 2019, 'Increased miR-142-3p Expression Might Explain Reduced Regulatory T Cell Function in Granulomatosis With Polyangiitis', Frontiers in Immunology, vol. 10, 2170. https://doi.org/10.3389/fimmu.2019.02170

Standard

Increased miR-142-3p Expression Might Explain Reduced Regulatory T Cell Function in Granulomatosis With Polyangiitis. / Dekkema, Gerjan J.; Bijma, Theo; Jellema, Pytrick G.; Van Den Berg, Anke; Kroesen, Bart-Jan; Stegeman, Coen A.; Heeringa, Peter; Abdulahad, Wayel H.; Sanders, Jan-Stephan.

In: Frontiers in Immunology, Vol. 10, 2170, 12.09.2019.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

Dekkema GJ, Bijma T, Jellema PG, Van Den Berg A, Kroesen B-J, Stegeman CA et al. Increased miR-142-3p Expression Might Explain Reduced Regulatory T Cell Function in Granulomatosis With Polyangiitis. Frontiers in Immunology. 2019 Sep 12;10. 2170. https://doi.org/10.3389/fimmu.2019.02170


BibTeX

@article{bf006cd8ed4c474ea47a63630db358ec,
title = "Increased miR-142-3p Expression Might Explain Reduced Regulatory T Cell Function in Granulomatosis With Polyangiitis",
abstract = "Objectives: Regulatory T cells (Tregs) are frequently functionally impaired in patients with granulomatosis with polyangiitis (GPA). However, the mechanism underlying their impaired function is unknown. Here, we hypothesized that Treg dysfunction in GPA is due to altered microRNA (miRNA) expression.Methods: RNA isolated from FACS-sorted memory ((M)) Tregs (CD4(+)CD45RO(+)CD25(+)CD127(-)) of 8 healthy controls (HCs) and 8 GPA patients without treatment was subjected to miRNA microarray analysis. Five differentially expressed miRNAs were validated in a larger cohort by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). An miRNA target gene database search revealed targets that were tested with RT-qPCR in (M)Tregs from patients and HCs. cAMP levels were measured using flow cytometry.Results: Microarray analysis revealed 19 differentially expressed miRNAs, of which miR-142-3p was confirmed to be significantly upregulated in (M)Tregs from GPA patients compared to those from HCs (1.9-fold, p = 0.03). In vitro overexpression of miR-142-3p lowered the suppressive capacity of (M)Tregs (2.1-fold, p = 0.03), and miR-142-3p expression correlated negatively with the suppressive capacity (rho = -0.446, p = 0.04). Overexpression of miR-142-3p significantly decreased cAMP levels (p = 0.02) and tended to decrease the mRNA levels of a predicted target gene, adenylate cyclase 9 (ADCY9; p = 0.06). In comparison to those from HCs, (M)Tregs from GPA patients had lower ADCY9 mRNA levels (2-fold, p = 0.008) and produced significantly less cAMP after stimulation. Importantly, induction of cAMP production in miR-142-3p overexpressed (M)Tregs by forskolin restored their suppressive function in vitro.Conclusion: Overexpression of miR-142-3p in (M)Tregs from GPA patients might cause functional impairment by targeting ADCY9, which leads to the suppression of cAMP production.",
keywords = "ANCA-associated vasculitis, Treg-regulatory T cell, auto immune, microRNA, suppressive function, CYCLIC ADENOSINE-MONOPHOSPHATE, SYSTEMIC-LUPUS-ERYTHEMATOSUS, WEGENERS-GRANULOMATOSIS, DISEASE-ACTIVITY, CD4+T CELLS, DIFFERENTIATION, VASCULITIS, PATHOGENESIS, SUPPRESSION",
author = "Dekkema, {Gerjan J.} and Theo Bijma and Jellema, {Pytrick G.} and {Van Den Berg}, Anke and Bart-Jan Kroesen and Stegeman, {Coen A.} and Peter Heeringa and Abdulahad, {Wayel H.} and Jan-Stephan Sanders",
note = "Copyright {\circledC} 2019 Dekkema, Bijma, Jellema, Van Den Berg, Kroesen, Stegeman, Heeringa, Abdulahad and Sanders.",
year = "2019",
month = "9",
day = "12",
doi = "10.3389/fimmu.2019.02170",
language = "English",
volume = "10",
journal = "Frontiers in Immunology",
issn = "1664-3224",
publisher = "Frontiers Media SA",

}

RIS

TY - JOUR

T1 - Increased miR-142-3p Expression Might Explain Reduced Regulatory T Cell Function in Granulomatosis With Polyangiitis

AU - Dekkema, Gerjan J.

AU - Bijma, Theo

AU - Jellema, Pytrick G.

AU - Van Den Berg, Anke

AU - Kroesen, Bart-Jan

AU - Stegeman, Coen A.

AU - Heeringa, Peter

AU - Abdulahad, Wayel H.

AU - Sanders, Jan-Stephan

N1 - Copyright © 2019 Dekkema, Bijma, Jellema, Van Den Berg, Kroesen, Stegeman, Heeringa, Abdulahad and Sanders.

PY - 2019/9/12

Y1 - 2019/9/12

N2 - Objectives: Regulatory T cells (Tregs) are frequently functionally impaired in patients with granulomatosis with polyangiitis (GPA). However, the mechanism underlying their impaired function is unknown. Here, we hypothesized that Treg dysfunction in GPA is due to altered microRNA (miRNA) expression.Methods: RNA isolated from FACS-sorted memory ((M)) Tregs (CD4(+)CD45RO(+)CD25(+)CD127(-)) of 8 healthy controls (HCs) and 8 GPA patients without treatment was subjected to miRNA microarray analysis. Five differentially expressed miRNAs were validated in a larger cohort by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). An miRNA target gene database search revealed targets that were tested with RT-qPCR in (M)Tregs from patients and HCs. cAMP levels were measured using flow cytometry.Results: Microarray analysis revealed 19 differentially expressed miRNAs, of which miR-142-3p was confirmed to be significantly upregulated in (M)Tregs from GPA patients compared to those from HCs (1.9-fold, p = 0.03). In vitro overexpression of miR-142-3p lowered the suppressive capacity of (M)Tregs (2.1-fold, p = 0.03), and miR-142-3p expression correlated negatively with the suppressive capacity (rho = -0.446, p = 0.04). Overexpression of miR-142-3p significantly decreased cAMP levels (p = 0.02) and tended to decrease the mRNA levels of a predicted target gene, adenylate cyclase 9 (ADCY9; p = 0.06). In comparison to those from HCs, (M)Tregs from GPA patients had lower ADCY9 mRNA levels (2-fold, p = 0.008) and produced significantly less cAMP after stimulation. Importantly, induction of cAMP production in miR-142-3p overexpressed (M)Tregs by forskolin restored their suppressive function in vitro.Conclusion: Overexpression of miR-142-3p in (M)Tregs from GPA patients might cause functional impairment by targeting ADCY9, which leads to the suppression of cAMP production.

AB - Objectives: Regulatory T cells (Tregs) are frequently functionally impaired in patients with granulomatosis with polyangiitis (GPA). However, the mechanism underlying their impaired function is unknown. Here, we hypothesized that Treg dysfunction in GPA is due to altered microRNA (miRNA) expression.Methods: RNA isolated from FACS-sorted memory ((M)) Tregs (CD4(+)CD45RO(+)CD25(+)CD127(-)) of 8 healthy controls (HCs) and 8 GPA patients without treatment was subjected to miRNA microarray analysis. Five differentially expressed miRNAs were validated in a larger cohort by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). An miRNA target gene database search revealed targets that were tested with RT-qPCR in (M)Tregs from patients and HCs. cAMP levels were measured using flow cytometry.Results: Microarray analysis revealed 19 differentially expressed miRNAs, of which miR-142-3p was confirmed to be significantly upregulated in (M)Tregs from GPA patients compared to those from HCs (1.9-fold, p = 0.03). In vitro overexpression of miR-142-3p lowered the suppressive capacity of (M)Tregs (2.1-fold, p = 0.03), and miR-142-3p expression correlated negatively with the suppressive capacity (rho = -0.446, p = 0.04). Overexpression of miR-142-3p significantly decreased cAMP levels (p = 0.02) and tended to decrease the mRNA levels of a predicted target gene, adenylate cyclase 9 (ADCY9; p = 0.06). In comparison to those from HCs, (M)Tregs from GPA patients had lower ADCY9 mRNA levels (2-fold, p = 0.008) and produced significantly less cAMP after stimulation. Importantly, induction of cAMP production in miR-142-3p overexpressed (M)Tregs by forskolin restored their suppressive function in vitro.Conclusion: Overexpression of miR-142-3p in (M)Tregs from GPA patients might cause functional impairment by targeting ADCY9, which leads to the suppression of cAMP production.

KW - ANCA-associated vasculitis

KW - Treg-regulatory T cell

KW - auto immune

KW - microRNA

KW - suppressive function

KW - CYCLIC ADENOSINE-MONOPHOSPHATE

KW - SYSTEMIC-LUPUS-ERYTHEMATOSUS

KW - WEGENERS-GRANULOMATOSIS

KW - DISEASE-ACTIVITY

KW - CD4+T CELLS

KW - DIFFERENTIATION

KW - VASCULITIS

KW - PATHOGENESIS

KW - SUPPRESSION

U2 - 10.3389/fimmu.2019.02170

DO - 10.3389/fimmu.2019.02170

M3 - Article

VL - 10

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

M1 - 2170

ER -

ID: 97952407